Pyroptotic cell death defends against intracellular pathogens

Inflammatory caspases play a central role in innate immunity by responding to cytosolic signals and initiating a twofold response. First, caspase-1 induces the activation and secretion of the two prominent pro-inflammatory cytokines, interleukin-1β (IL-1β) and IL-18. Second, either caspase-1 or caspase-11 can trigger a form of lytic, programmed cell death called pyroptosis. Pyroptosis operates to remove the replication niche of intracellular pathogens, making them susceptible to phagocytosis and killing by a secondary phagocyte. However, aberrant, systemic activation of pyroptosis in vivo may contribute to sepsis. Emphasizing the efficiency of inflammasome detection of microbial infections, many pathogens have evolved to avoid or subvert pyroptosis. This review focuses on molecular and morphological characteristics of pyroptosis and the individual inflammasomes and their contribution to defense against infection in mice and humans.     

细胞焦亡：程序性死亡研究新热点

细胞焦亡(Pyroptosis)是一种以促炎性为特点的细胞程序性死亡方式,分为依赖半胱氨酸蛋白酶-1(Caspase-1)的经典细胞焦亡途径和依赖半胱氨酸蛋白酶-4/5/11(Caspase-4/5/11)的非经典细胞焦亡途径。研究表明细胞焦亡广泛参与到多种疾病的发生发展中。最近研究人员发现GSDMD和Pannexin-1可能是介导细胞焦亡的关键物质,但具体机制和相互关系仍有待进一步深入研究。     

Nitrosonisoldipine is a selective inhibitor of inflammatory caspases and protects against pyroptosis and related septic shock

Pyroptosis is a type of acute cell death that mainly occurs in immune cells. It is characterized with robust release of inflammatory cytokines and has emerged to play a critical role in the pathogenesis of sepsis-associated immune disorders. In this study, we screened for pyroptotic inhibitors with the ultimate goal to benefit sepsis treatments. Accidentally, we identified that nitrosonisoldipine (NTS), a photodegradation product of calcium channel inhibitor nisoldipine, inhibits noncanonical pyroptosis. Using murine immortalized BM-derived macrophage and human THP-1 cell line, we further discovered that NTS not only inhibits noncanonical pyroptosis mediated by caspase-11 or caspase-4 but also canonical pyroptosis mediated by caspase-1. Mechanistically, NTS directly inhibits the enzyme activities of these inflammatory caspases, and these inhibitory effects persist despite extensive washout of the drug. By contrast, apoptosis mediated by caspase-3/-7 was not affected by NTS. Mice pretreated with NTS intraperitoneally displayed improved survival rate and extended survival time in LPS- and polymicrobe-induced septic models, respectively. In conclusion, NTS is a selective inhibitor of inflammatory caspases that blocks both the noncanonical and canonical pyroptotic pathways. It is safe for intraperitoneal administration and might be used as a prototype to develop drugs for sepsis treatments.     

Caspase-1-induced pyroptotic cell death

Programmed cell death is a necessary part of development and tissue homeostasis enabling the removal of unwanted cells. In the setting of infectious disease, cells that have been commandeered by microbial pathogens become detrimental to the host. When macrophages and dendritic cells are compromised in this way, they can be lysed by pyroptosis, a cell death mechanism that is distinct from apoptosis and oncosis/necrosis. Pyroptosis is triggered by Caspase-1 after its activation by various inflammasomes and results in lysis of the affected cell. Both pyroptosis and apoptosis are programmed cell death mechanisms but are dependent on different caspases, unlike oncosis. Similar to oncosis and unlike apoptosis, pyroptosis results in cellular lysis and release of the cytosolic contents to the extracellular space. This event is predicted to be inherently inflammatory and coincides with interleukin-1β (IL-1β) and IL-18 secretion. We discuss the role of distinct inflammasomes, including NLRC4, NLRP3, and AIM2, as well as the role of the ASC focus in Caspase-1 signaling. We further review the importance of pyroptosis in vivo as a potent mechanism to clear intracellular pathogens.     

细胞焦亡在肾脏炎性损伤中的作用研究进展

细胞焦亡(pyroptoysis)是由活化的caspase-1触发的一种特殊的细胞程序性死亡。肾脏细胞焦亡在肾损伤中发挥着重要的作用。GSDMD切割焦亡关键蛋白caspase-1引起下游炎性反应因子IL-18,IL-1β的成熟和释放引起肾脏炎性反应和细胞焦亡发生。本文从NLRP3激活导致肾脏炎性反应、GSDMD裂解引发细胞焦亡等角度,阐释NLRP3-caspase-1-GSDMD介导的细胞焦亡在肾脏炎性反应中的作用。     

焦亡信号通路炎症小体与中枢神经系统疾病研究进展

焦亡是一种新发现并证实与炎症相关的细胞死亡方式,其特征为依赖于半胱天冬氨酸蛋白酶-1(caspase-1)的细胞程序性死亡,并伴有促炎症因子的释放,主要为白细胞介素1β和IL-18.虽然焦亡与坏死和凋亡有相似之处,但它们是迥然不同的生物学过程.越来越多的研究发现,焦亡相关信号通路在中枢神经系统疾病中起重要作用,包括急性脑感染、神经变性疾病、急性无菌性脑损伤和慢性无菌性中枢神经系统炎症.     

Research progresses of molecular mechanism of pyroptosis and its related diseases

Pyroptosis is a newly discovered untypical form of programmed cell death by inflammatory response, which is dependent on the classic pathway of Caspase-1 and the non-canonical pathway of Caspase-11 in mice or orthologue Caspase-4/-5 in Humans. It has been found that the Gasdermin family of protein is a key molecule in the formation of membrane pores of pyroptosis. After being cleaved by inflammatory caspases, it releases a N-terminal fragment with perforating activity to trigger pyroptosis. That pyroptosis is closely related to the occurrence and development of certain diseases. Now, the molecular mechanism of pyroptosis and pyroptosis-related diseases are reviewed.     

Statins as anti-pyroptotic agents

IntroductionPyroptosis is a regulated form of cell death, which is often a consequence of the activation of inflammatory caspases.MethodsAppropriate inflammatory responses and the induction of pyroptosis enhance the clearance of pathogens and increase innate immunity.ResultsHowever, excessive pyroptosis contributes to a hyperinflammatory response and aggravates tissue damage, thereby causing inflammatory diseases. There have been recent reports on the modulation of pyroptosis by statins, which may explain part of the pleiotropic actions of these drugs in inflammatory diseases and cancer.ConclusionsHerein, the extant evidence for the potential value of statins in targeting pyroptosis in various diseases is reviewed.     

Pyroptosis in neutrophils: Multimodal integration of inflammasome and regulated cell death signaling pathways

Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin-family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination of intracellular replicative niches for pathogenic bacteria; and (ii) non-classical secretion of IL-1 family cytokines that amplify host-beneficial inflammatory responses to microbial infection or tissue damage. Physiological roles for gasdermin D (GSDMD) in pyroptosis and IL-1β release during inflammasome signaling have been extensively characterized in macrophages. This involves cleavage of GSDMD by caspase-1 to generate GSDMD macropores that mediate IL-1β efflux and progression to pyroptotic lysis. Neutrophils, which rapidly accumulate in large numbers at sites of tissue infection or damage, become the predominant local source of IL-1β in coordination with their potent microbiocidal capacity. Similar to macrophages, neutrophils express GSDMD and utilize the same spectrum of diverse inflammasome platforms for caspase-1-mediated cleavage of GSDMD. Distinct from macrophages, neutrophils possess a remarkable capacity to resist progression to GSDMD-dependent pyroptotic lysis to preserve their viability for efficient microbial killing while maintaining GSDMD-dependent mechanisms for export of bioactive IL-1β. Rather, neutrophils employ cell-specific mechanisms to conditionally engage GSDMD-mediated pyroptosis in response to bacterial pathogens that use neutrophils as replicative niches. GSDMD and pyroptosis have also been mechanistically linked to induction of NETosis, a signature neutrophil pathway that expels decondensed nuclear DNA into extracellular compartments for immobilization and killing of microbial pathogens. This review summarizes a rapidly growing number of recent studies that have produced new insights, unexpected mechanistic nuances, and some controversies regarding the regulation of, and roles for, neutrophil inflammasomes, pyroptosis, and GSDMs in diverse innate immune responses.     

Fusobacterium nucleatum infection activates the noncanonical inflammasome and exacerbates inflammatory response in DSS-induced colitis

Caspase activation results in pyroptosis, an inflammatory cell death that contributes to several inflammatory diseases by releasing inflammatory cytokines and cellular contents. Fusobacterium nucleatum is a periodontal pathogen frequently detected in human cancer and inflammatory bowel diseases. Studies have reported that F. nucleatum infection leads to NLRP3 activation and pyroptosis, but the precise activation process and disease association remain poorly understood. This study demonstrated that F. nucleatum infection exacerbates acute colitis in mice and activates pyroptosis through caspase-11-mediated gasdermin D cleavage in macrophages. Furthermore, F. nucleatum infection in colitis mice induces the enhancement of IL-1⍺ secretion from the colon, affecting weight loss and severe disease activities. Neutralization of IL-1⍺ protects F. nucleatum infected mice from severe colitis. Therefore, F. nucleatum infection facilitates inflammation in acute colitis with IL-1⍺ from colon tissue by activating noncanonical inflammasome through gasdermin D cleavage.     

心肌缺血再灌注损伤中细胞焦亡的研究进展

细胞焦亡是近年来发现并被证实的一种新的细胞程序性死亡方式,它的特征是依赖半胱氨酸天冬氨酸酶1(cysteinyl aspartate specific proteinase 1,caspase-1)并伴随大量炎症因子的释放。细胞焦亡参与了包括感染性疾病在内的多种疾病的病理生理过程。作为一种新的调节性细胞死亡方式,近年来细胞焦亡受到了广泛的关注。新近研究发现,细胞焦亡也参与了心肌缺血再灌注损伤(myocardial ischemia reperfusion injury,MIRI)过程,文章就MIRI中细胞焦亡的研究进展进行综述。     

Involvement of caspase-4 in IL-1 beta production and pyroptosis in human macrophages during dengue virus infection

Caspase-4 physically interacts with caspase-1 and is believed to be a proinflammatory caspase that can induce the inflammatory form of programmed cell death (pyroptosis) and the release of mature interleukin (IL)-1β. However, the function of caspase-4 in dengue virus infection is not yet fully understood. We examined the function of caspase-4 in IL-1β production and pyroptosis during dengue virus serotype-2 (DENV-2) infection in human macrophages. In this study, DENV-2 infection increased IL-1β protein level with activated caspase-4 activity. Using primary macrophages, we observed that caspase-4 induces activation of caspase-1 and secretion of IL-1β in response to DENV-2 infection, without the need for secondary signals to stimulate the assembly of the inflammasome. These findings indicate that the regulation of caspase-1 activity by capsase-4 could represent a unique mechanism. Our data suggest that caspase-4 is upstream of caspase-1 in the pathway that regulates pyroptosis and IL-1β synthesis in macrophages during DENV-2 infection.     

Salmonella-induced inflammasome activation in humans

Inflammasomes are macromolecular complexes that assemble upon recognition of pathogen- or danger-associated molecular patterns. Inflammasome assembly is nucleated by the oligomerisation of specific, activated pattern recognition receptors within the cytosol. Inflammasomes function as platforms for the activation of the caspase-1 protease, which in turn triggers the maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18, and initiates pyroptosis, a highly inflammatory form of lytic cell death. Recently, additional inflammatory caspases (murine caspase-11, and human caspase-4/5) were also reported to be activated upon a pyroptosis-inducing ‘non-canonical inflammasome’ by direct recognition of lipopolysaccharide (LPS), a pathogen-associated molecular pattern. Here we review and discuss recent advances in our understanding of inflammasome-mediated host defence against Salmonella particularly in human cells, and their implications for cellular survival and cytokine secretion.     

NLR-mediated control of inflammasome assembly in the host response against bacterial pathogens

The host response against diverse bacterial pathogens involves activation of specialized immune cells and elaboration of pro-inflammatory cytokines that help to coordinate appropriate host defense. Members of the interleukin-1 (IL-1) cytokine family, IL-1β and IL-18, are central players in this process. Extracellular release of the mature, active form of these cytokines requires their processing by the cysteine protease caspase-1, which therefore serves as a key regulator of the inflammatory response. In addition to its role in secretion of pro-inflammatory cytokines, caspase-1 is also required for a form of cell death, recently termed pyroptosis, that occurs in macrophages infected by certain bacterial pathogens. Caspase-1 itself is synthesized as a pro-enzyme, which must first be activated by autocatalytic cleavage. This activation requires recruitment of caspase-1 into multiprotein complexes known as inflammasomes. The Nod-like receptor (NLR) family of cytosolic proteins play an important role in detecting inflammatory stimuli and subsequently mediate inflammasome assembly. A common feature of NLR proteins that trigger inflammasome assembly in response to bacterial infection is that they appear to sense membrane perturbation or delivery of bacterial components into the cytosol through bacterial pore-forming toxins or bacterial secretion systems. This review will discuss the recent developments regarding caspase-1 activation in response to bacterial infection, cross-talk between caspase-1 and other pathways involved in regulating cell death, and recent findings that a number of bacterial pathogens possess mechanisms to inhibit caspase-1 activation.     

Macrophages and Recently Identified Forms of Cell Death

Recent advances in cell death biology have uncovered an ever increasing range of cell death forms. Macrophages have a bidirectional relationship with cell death that modulates the immune response. Thus, macrophages engulf apoptotic cells and secrete cytokines that may promote cell death in parenchymal cells. Furthermore, the presence of apoptotic or necrotic dead cells in the microenvironment elicits differential macrophage responses. Apoptotic cells elicit anti-inflammatory responses in macrophages. By contrast macrophages may undergo a proinflammatory form of cell death (pyroptosis) in response to damage-associated molecular patterns (DAMPs) released from necrotic cells and also in response to pathogen-associated molecular patterns (PAMPs). Pyroptosis is a recently identified form of cell death that occurs predominantly in subsets of inflammatory macrophages and is associated to the release of interleukin-1β (IL-1β) and IL-18. Deregulation of these processes may result in disease. Thus, failure of macrophages to engulf apoptotic cells may be a source of autoantigens in autoimmune diseases, excessive macrophage release of proapoptotic factors or sterile pyroptosis may contribute to tissue injury and failure of pathogen-induced pyroptosis may contribute to pathogen survival. Ongoing research is exploring the therapeutic opportunities resulting this new knowledge.     

Pyroptosis in cardiovascular diseases: Pumping gasdermin on the fire

Pyroptosis is a form of programmed cell death associated with activation of inflammasomes and inflammatory caspases, proteolytic cleavage of gasdermin proteins (forming pores in the plasma membrane), and selective release of proinflammatory mediators. Induction of pyroptosis results in amplification of inflammation, contributing to the pathogenesis of chronic cardiovascular diseases such as atherosclerosis and diabetic cardiomyopathy, and acute cardiovascular events, such as thrombosis and myocardial infarction. While engagement of pyroptosis during sepsis-induced cardiomyopathy and septic shock is expected and well documented, we are just beginning to understand pyroptosis involvement in the pathogenesis of cardiovascular diseases with less defined inflammatory components, such as atrial fibrillation. Due to the danger that pyroptosis represents to cells within the cardiovascular system and the whole organism, multiple levels of pyroptosis regulation have evolved. Those include regulation of inflammasome priming, post-translational modifications of gasdermins, and cellular mechanisms for pore removal. While pyroptosis in macrophages is well characterized as a dramatic pro-inflammatory process, pyroptosis in other cell types within the cardiovascular system displays variable pathways and consequences. Furthermore, different cells and organs engage in local and distant crosstalk and exchange of pyroptosis triggers (oxidized mitochondrial DNA), mediators (IL-1β, S100A8/A9) and antagonists (IL-9). Development of genetic tools, such as Gasdermin D knockout animals, and small molecule inhibitors of pyroptosis will not only help us fully understand the role of pyroptosis in cardiovascular diseases but may result in novel therapeutic approaches inhibiting inflammation and progression of chronic cardiovascular diseases to reduce morbidity and mortality from acute cardiovascular events.     

Pyroptosis modulation by bacterial effector proteins

Pyroptosis is a proinflammatory form of programmed cell death featured with membrane pore formation that causes cellular swelling and allows the release of intracellular inflammatory mediators. This cell death process is elicited by the activation of the pore-forming proteins named gasdermins, and is intricately orchestrated by diverse regulatory factors in mammalian hosts to exert a prompt immune response against infections. However, growing evidence suggests that bacterial pathogens have evolved to regulate host pyroptosis for evading immune clearance and establishing progressive infection. In this review, we highlight current understandings of the functional role and regulatory network of pyroptosis in host antibacterial immunity. Thereafter, we further discuss the latest advances elucidating the mechanisms by which bacterial pathogens modulate pyroptosis through adopting their effector proteins to drive infections. A better understanding of regulatory mechanisms underlying pyroptosis at the interface of host-bacterial interactions will shed new light on the pathogenesis of infectious diseases and contribute to the development of promising therapeutic strategies against bacterial pathogens.     

Caspase-11在固有免疫中的作用

半胱氨酸的天冬氨酸蛋白水解酶Caspase-11与胞内宿主炎症模式识别受体(host pattern recognition receptors,PRR)、炎症小体转接器ASC三部分组成caspase-11炎性小体复合物,被脂多糖的6-乙酰基脂质A识别,进而激活机体固有免疫应答反应.细胞内吞脂多糖(lipopolysaccharide,LPS)后,caspase-11在细胞质内特异识别定位的何种细胞器一直未有明确定论,为精准地靶向定位带来一些困难.脂多糖激活caspase-11可以导致IL-I β/IL-18相关的炎性反应及pannexin-1、GSDMD介导细胞焦亡.Caspase-11的胞内信号靶点探索,将是未来某些疾病治疗新的研究方向,如结肠癌、GSDMD相关的脱毛症等.     

细胞焦亡:一种新的细胞死亡方式

细胞焦亡是近年来发现并证实的一种新的程序性细胞死亡方式,其特征为依赖于半胱天冬酶-1(caspase-1),并伴有大量促炎症因子的释放.细胞焦亡的形态学特征、发生及调控机制等均不同于凋亡、坏死等其他细胞死亡方式.研究表明,细胞焦亡广泛参与感染性疾病、神经系统相关疾病和动脉粥样硬化性疾病等的发生发展,并发挥重要作用.对细...     

Nutlin-3 促进肝癌细胞SMMC-7721 发生焦亡的作用

目的:探讨MDM2 拮抗剂Nutlin-3 促进肝癌细胞SMMC-7721 发生焦亡的作用及相关机制。方法:Western blot 检测细胞中活化caspase-1(p20)及IL-1β的表达,LDH 法检测SMMC-7721 细胞焦亡情况,ELISA 检测细胞上清中IL-1β释放情况。结果:Nutlin-3 提高SMMC-7721 细胞活化caspase-1(p20) 及IL-1β的蛋白表达水平。Nutlin-3 处理显著提高了SMMC-7721 细胞培养上清中的LDH 及IL-1β的表达水平(P<0.05)。结论:Nutlin-3 激活了caspase-1,诱导肝癌细胞SMMC- 7721 发生焦亡,并促进IL-1β释放。